Knowing the enemy: strategic targeting of complement to treat Alzheimer disease

Abstract

The complement system protects against infection, positively responds to tissue damage, clears cell debris, directs and modulates the adaptive immune system, and functions in neuronal development, normal synapse elimination and intracellular metabolism. However, complement also has a role in aberrant synaptic pruning and neuroinflammation — processes that lead to a feedforward loop of inflammation, injury and neuronal death that can contribute to neurodegenerative and neurological disorders, including Alzheimer disease. This Review provides justification, largely from preclinical mouse models but also from correlates with human tissue and biomarkers, for targeting specific complement components for therapeutic intervention in Alzheimer disease. We discuss promising strategies to slow the progression of cognitive loss with minimal undesired effects. The diverse interactions and functions of complement system components can influence biological processes in the healthy and diseased brain; here, these functions are described as a prerequisite to selecting appropriate, safe and effective therapeutic targets for translation to the clinic. The complement system has important roles in a variety of physiological processes, but it can also contribute to neurodegenerative diseases such as Alzheimer disease through excessive synaptic pruning and neuroinflammation. In this Review, the authors explore the therapeutic potential of targeting specific complement components for the treatment of Alzheimer disease.